Globotriaosylceramide leads to KCa3.1 channel dysfunction: A new insight into endothelial dysfunction in Fabry disease

Seonghee Park, Ji Aee Kim, Ka Young Joo, Shinkyu Choi, Eun Nam Choi, Jung A. Shin, Ki Hwan Han, Sung Chul Jung, Suk Hyo Suh

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

AimsExcessive endothelial globotriaosylceramide (Gb3) accumulation is associated with endothelial dysfunction and impaired endothelium-dependent relaxation in Fabry disease. In endothelial cells, KCa3.1 channels contribute to endothelium-dependent relaxation. However, the effect of Gb3 on KCa3.1 channels and the underlying mechanisms of Gb3-induced dysfunction are unknown. Herein, we hypothesized that Gb3 accumulation induces KCa3.1 channel dysfunction and aimed to clarify the underlying mechanisms. Methods and resultsThe animal model of Fabry disease, α-galactosidase A (Gla) knockout mice, displayed age-dependent KCa3.1 channel dysfunction. KCa3.1 current and the channel expression were significantly reduced in mouse aortic endothelial cells (MAECs) of aged Gla knockout mice, whereas they were not changed in MAECs of wild-type and young Gla knockout mice. In addition, KCa3.1 current and the channel expression were concentration-dependently reduced in Gb3-treated MAECs. In both Gb3-treated and aged Gla knockout MAECs, extracellular signal-regulated kinase (ERK) and activator protein-1 (AP-1) were down-regulated and repressor element-1 silencing transcription factor (REST) was up-regulated. Gb3 inhibited class III phosphoinositide 3-kinase and decreased intracellular levels of phosphatidylinositol 3-phosphate [PI(3)P]. In addition, endothelium-dependent relaxation was significantly attenuated in Gb3-treated mouse aortic rings. ConclusionGb3 accumulation reduces KCa3.1 channel expression by down-regulating ERK and AP-1 and up-regulating REST and the channel activity by decreasing intracellular levels of PI(3)P. Gb3 thereby evokes KCa3.1 channel dysfunction, and the channel dysfunction in vascular endothelial cells may contribute to vasculopathy in Fabry disease.

Original languageEnglish
Pages (from-to)290-299
Number of pages10
JournalCardiovascular Research
Volume89
Issue number2
DOIs
StatePublished - 1 Feb 2011

Keywords

  • α-Galactosidase A knockout mice
  • Endothelial dysfunction
  • Fabry disease
  • Globotriaosylceramide
  • KCa3.1 channel

Fingerprint

Dive into the research topics of 'Globotriaosylceramide leads to KCa3.1 channel dysfunction: A new insight into endothelial dysfunction in Fabry disease'. Together they form a unique fingerprint.

Cite this